Cystatin C

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Cystatin C or cystatin 3 (formerly gamma trace, post-gamma-globulin, or neuroendocrine basic polypeptide),[1] a protein encoded by the CST3 gene, is mainly used as a biomarker of kidney function. Recently, it has been studied for its role in predicting new-onset or deteriorating cardiovascular disease. It also seems to play a role in brain disorders involving amyloid (a specific type of protein deposition), such as Alzheimer's disease. In humans, all cells with a nucleus (cell core containing the DNA) produce cystatin C as a chain of 120 amino acids. It is found in virtually all tissues and body fluids. It is a potent inhibitor of lysosomal proteinases (enzymes from a special subunit of the cell that break down proteins) and probably one of the most important extracellular inhibitors of cysteine proteases (it prevents the breakdown of proteins outside the cell by a specific type of protein degrading enzymes). Cystatin C belongs to the type 2 cystatin gene family.

Gene

Transcriptions

The "four cystatin genes [GeneID: 1469 CST1, GeneID: 1470 CST2, GeneID: 1471 CST3, and GeneID: 1472 CST4] contain the ATA-box sequence (ATAAA) in their 5'-flanking regions; however, the CAT-box sequence (CAT), a binding site of the transcription factor, CTF, is found only in the 5'-flanking region of the S-type cystatin genes."[2]

Role in medicine

Kidney function

See also: Renal function

Glomerular filtration rate (GFR), a marker of kidney health, is most accurately measured by injecting compounds such as inulin, radioisotopes such as 51chromium-EDTA, 125I-iothalamate, 99mTc-DTPA or radiocontrast agents such as iohexol, but these techniques are complicated, costly, time-consuming and have potential side-effects.[3][4] Creatinine is the most widely used biomarker of kidney function. It is inaccurate at detecting mild renal impairment, and levels can vary with muscle mass but not with protein intake. Urea levels might change with protein intake.[5] Formulas such as the Cockcroft and Gault formula and the MDRD formula (see Renal function) try to adjust for these variables.

Cystatin C has a low molecular weight (approximately 13.3 kilodaltons), and it is removed from the bloodstream by glomerular filtration in the kidneys. If kidney function and glomerular filtration rate decline, the blood levels of cystatin C rise. Cross-sectional studies (based on a single point in time) suggest that serum levels of cystatin C are a more precise test of kidney function (as represented by the glomerular filtration rate, GFR) than serum creatinine levels.[4][6]. Longitudinal studies (following cystatin C over time) are sparse, but some show promising results.[7][8][9] Cystatin C levels are less dependent on age, gender, ethnicity and muscle mass compared to creatinine. Cystatin C measurements alone have not been shown to be superior to formula-adjusted estimations of kidney function.[10] As opposed to previous claims, cystatin C has been found to be influenced by body composition.[11][12] It has been suggested that cystatin C might predict the risk of developing chronic kidney disease, thereby signaling a state of 'preclinical' kidney dysfunction.[13]

Studies have also investigated cystatin C as a marker of kidney function in the adjustment of medication dosages.[14][15]

Cystatin C levels have been reported to be altered in patients with cancer,[16][17][18] (even subtle) thyroid dysfunction[19][20][21] and glucocorticoid therapy in some[22][23] but not all[24] situations. Other reports have found that levels are influenced by cigarette smoking and levels of C-reactive protein.[25] Levels seem to be increased in HIV infection, which might or might not reflect actual renal dysfunction.[26][27][28] The role of cystatin C to monitor GFR during pregnancy remains controversial.[29][30] Like creatinine, the elimination of cystatin C via routes other than the kidney increase with worsening GFR.[31]

Death and cardiovascular disease

Kidney dysfunction increases the risk of death and cardiovascular disease.[32][33] Several studies have found that increased levels of cystatin C are associated with the risk of death, several types of cardiovascular disease (including myocardial infarction, stroke, heart failure, peripheral arterial disease and metabolic syndrome) and healthy aging.[citation needed][clarification needed] Some studies have found cystatin C to be better in this regard than serum creatinine or creatinine-based GFR equations.[34][35][36][37][38][39][40][41][42][43][44][45] Because the association of cystatin C with long term outcomes has appeared stronger than what could be expected for GFR, it has been hypothesized that cystatin C might also be linked to mortality in a way independent of kidney function.[46] In keeping with its housekeeping gene properties, it has been suggested that cystatin C might be influenced by the basal metabolic rate.[47]

Neurologic disorders

Mutations in the cystatin 3 gene are responsible for the Icelandic type of hereditary cerebral amyloid angiopathy, a condition predisposing to intracerebral haemorrhage, stroke and dementia.[48][49] The condition is inherited in a dominant fashion.

Since cystatin 3 also binds amyloid β and reduces its aggregation and deposition, it is a potential target in Alzheimer's disease.[50][51] Although not all studies have confirmed this, the overall evidence is in favor of a role for CST3 as a susceptibility gene for Alzheimer's disease.[52] Cystatin C levels have been reported to be higher in subjects with Alzheimer's disease.[53]

The role of cystatin C in multiple sclerosis and other demyelinating diseases (characterized by a loss of the myelin nerve sheath) remains controversial.[54]

Other roles

Cystatin C levels are decreased in atherosclerotic (so-called 'hardening' of the arteries) and aneurysmal (saccular bulging) lesions of the aorta.[55][56][57][58] Genetic and prognostic studies also suggest a role for cystatin C.[59][60] Breakdown of parts of the vessel wall in these conditions is thought to result from an imbalance between proteinases (cysteine proteases and matrix metalloproteinases, increased) and their inhibitors (such as cystatin C, decreased).

A few studies have looked at the role of cystatin C or the CST3 gene in age-related macular degeneration.[61][62] Cystatin C has also been investigated as a prognostic marker in several forms of cancer.[63][64] Its role in pre-eclampsia remains to be confirmed.[65][66][67][68]

Laboratory measurement

Cystatin C can be measured in a random sample of serum (the fluid in blood from which the red blood cells and clotting factors have been removed) using immunoassays such as nephelometry or particle-enhanced turbidimetry.[69] It is a more expensive test than serum creatinine (around $2 or $3, compared to $0.02 to $0.15), which can be measured with a Jaffé reaction.[70][71][72]

Reference values differ in many populations and with sex and age. Across different studies, the mean reference interval (as defined by the 5th and 95th percentile) was between 0.52 and 0.98 mg/L. For women, the average reference interval is 0.52 to 0.90 mg/L with a mean of 0.71 mg/L. For men, the average reference interval is 0.56 to 0.98 mg/L with a mean of 0.77 mg/L.[69] The normal values decrease until the first year of life, remaining relatively stable before they increase again, especially beyond age 50.[73][74][75] Creatinine levels increase until puberty and differ according to gender from then on, making their interpretation problematic for pediatric patients.[74][76]

In a large study from the United States National Health and Nutrition Examination Survey, the reference interval (as defined by the 1st and 99th percentile) was between 0.57 and 1.12 mg/L. This interval was 0.55 - 1.18 for women and 0.60 - 1.11 for men. Non-Hispanic blacks and Mexican Americans had lower normal cystatin C levels.[73] Other studies have found that in patients with an impaired renal function, women have lower and blacks have higher cystatin C levels for the same GFR.[10] For example, the cut-off values of cystatin C for chronic kidney disease for a 60-year-old white women would be 1.12 mg/L and 1.27 mg/L in a black man (a 13% increase). For serum creatinine values adjusted with the MDRD equation, these values would be 0.95 mg/dL to 1.46 mg/dL (a 54% increase).[77]

Based on a threshold level of 1.09 mg/L (the 99th percentile in a population of 20- to 39-year-olds without hypertension, diabetes, microalbuminuria or macroalbuminuria or higher than stage 3 chronic kidney disease), the prevalence of increased levels of cystatin C in the United States was 9.6% in subjects of normal weight, increasing in overweight and obese individuals.[78] In Americans aged 60 and 80 and older, serum cystatin is increased in 41% and more than 50%.[73]

Molecular biology

The cystatin superfamily encompasses proteins that contain multiple cystatin-like sequences. Some of the members are active cysteine protease inhibitors, while others have lost or perhaps never acquired this inhibitory activity. There are three inhibitory families in the superfamily, including the type 1 cystatins (stefins), type 2 cystatins and the kininogens. The type 2 cystatin proteins are a class of cysteine proteinase inhibitors found in a variety of human fluids and secretions, where they appear to provide protective functions. The cystatin locus on the short arm of chromosome 20 contains the majority of the type 2 cystatin genes and pseudogenes.

The CST3 gene is located in the cystatin locus and comprises 3 exons (coding regions, as opposed to introns, non-coding regions within a gene), spanning 4.3 kilo-base pairs. It encodes the most abundant extracellular inhibitor of cysteine proteases. It is found in high concentrations in biological fluids and is expressed in virtually all organs of the body (CST3 is a housekeeping gene). The highest levels are found in semen, followed by breastmilk, tears and saliva. The hydrophobic leader sequence indicates that the protein is normally secreted. There are three polymorphisms in the promoter region of the gene, resulting in two common variants.[79] Several single nucleotide polymorphisms have been associated with altered cystatin C levels.[80]

Cystatin C is a non-glycosylated, basic protein (isoelectric point at pH 9.3). The crystal structure of cystatin C is characterized by a short alpha helix and a long alpha helix which lies across a large antiparallel, five-stranded beta sheet. Like other type 2 cystatins, it has two disulfide bonds. Around 50% of the molecules carry a hydroxylated proline. Cystatin C forms dimers (molecule pairs) by exchanging subdomains; in the paired state, each half is made up of the long alpha helix and one beta strand of one partner, and four beta strands of the other partner.[81]

History

Cystatin C was first described as 'gamma-trace' in 1961 as a trace protein together with other ones (such as beta-trace) in the cerebrospinal fluid and in the urine of patients with renal failure.[82] Grubb and Löfberg first reported its amino acid sequence.[82] They noticed it was increased in patients with advanced renal failure.[83] It was first proposed as a measure of glomerular filtration rate by Grubb and coworkers in 1985.[84][85]

Use of serum creatinine and cystatin C was found very effective in accurately reflecting the GFR in a study reported in the July 5, 2012 issue of the New England Journal of Medicine.[86]

Footnotes

  1. ↑ "Alzforum: AlzGene". Archived from the original on 2004-12-27.
  2. ↑ Eiichi Saitoh and Satoko Isemura (January 1, 1993). "Molecular Biology of Human Salivary Cysteine Proteinase Inhibitors" (PDF). Critical Reviews in Oral Biology and Medicine. 4 (3/4): 487–93. doi:10.1177/10454411930040033301. Retrieved 2013-06-28.
  3. ↑ Zahran A, El-Husseini A, Shoker A (2007). "Can cystatin C replace creatinine to estimate glomerular filtration rate? A literature review". Am. J. Nephrol. 27 (2): 197–205. doi:10.1159/000100907. PMID 17361076.
  4. ↑ 4.0 4.1 Roos JF, Doust J, Tett SE, Kirkpatrick CM (March 2007). "Diagnostic accuracy of cystatin C compared to serum creatinine for the estimation of renal dysfunction in adults and children--a meta-analysis". Clin. Biochem. 40 (5–6): 383–391. doi:10.1016/j.clinbiochem.2006.10.026. PMID 17316593.
  5. ↑ King AJ, Levey AS (May 1993). "Dietary protein and renal function". J. Am. Soc. Nephrol. 3 (11): 1723–37. PMID 8329667.
  6. ↑ Dharnidharka VR, Kwon C, Stevens G (August 2002). "Serum cystatin C is superior to serum creatinine as a marker of kidney function: a meta-analysis". Am. J. Kidney Dis. 40 (2): 221–226. doi:10.1053/ajkd.2002.34487. PMID 12148093.
  7. ↑ Premaratne E, MacIsaac RJ, Finch S, Panagiotopoulos S, Ekinci E, Jerums G (May 2008). "Serial measurements of cystatin C are more accurate than creatinine-based methods in detecting declining renal function in type 1 diabetes". Diabetes Care. 31 (5): 971–973. doi:10.2337/dc07-1588. PMID 18319326.
  8. ↑ Perkins BA, Nelson RG, Ostrander BE, et al. (May 2005). "Detection of renal function decline in patients with diabetes and normal or elevated GFR by serial measurements of serum cystatin C concentration: results of a 4-year follow-up study". J. Am. Soc. Nephrol. 16 (5): 1404–1412. doi:10.1681/ASN.2004100854. PMC 2429917. PMID 15788478.
  9. ↑ Corrao AM, Lisi G, Di Pasqua G, et al. (January 2006). "Serum cystatin C as a reliable marker of changes in glomerular filtration rate in children with urinary tract malformations". J. Urol. 175 (1): 303–309. doi:10.1016/S0022-5347(05)00015-7. PMID 16406933.
  10. ↑ 10.0 10.1 Stevens LA, Coresh J, Schmid CH, et al. (March 2008). "Estimating GFR using serum cystatin C alone and in combination with serum creatinine: a pooled analysis of 3,418 individuals with CKD". Am. J. Kidney Dis. 51 (3): 395–406. doi:10.1053/j.ajkd.2007.11.018. PMC 2390827. PMID 18295055.
  11. ↑ Shlipak MG (April 2007). "Cystatin C as a marker of glomerular filtration rate in chronic kidney disease: influence of body composition". Nat Clin Pract Nephrol. 3 (4): 188–189. doi:10.1038/ncpneph0404. PMID 17290239.
  12. ↑ Macdonald J, Marcora S, Jibani M, et al. (November 2006). "GFR estimation using cystatin C is not independent of body composition". Am. J. Kidney Dis. 48 (5): 712–719. doi:10.1053/j.ajkd.2006.07.001. PMID 17059990.
  13. ↑ Shlipak MG, Katz R, Sarnak MJ, et al. (August 2006). "Cystatin C and prognosis for cardiovascular and kidney outcomes in elderly persons without chronic kidney disease". Annals of Internal Medicine. 145 (4): 237–46. doi:10.7326/0003-4819-145-4-200608150-00003. PMID 16908914.
  14. ↑ Hermida J, Tutor JC (June 2006). "Serum cystatin C for the prediction of glomerular filtration rate with regard to the dose adjustment of amikacin, gentamicin, tobramycin, and vancomycin". Ther Drug Monit. 28 (3): 326–331. doi:10.1097/01.ftd.0000211805.89440.3d. PMID 16778715.
  15. ↑ Schück O, Teplan V, Sibová J, Stollová M (February 2004). "Predicting the glomerular filtration rate from serum creatinine, serum cystatin C and the Cockcroft and Gault formula with regard to drug dosage adjustment". Int J Clin Pharmacol Ther. 42 (2): 93–7. doi:10.5414/cpp42093. PMID 15180169.
  16. ↑ Demirtaş S, Akan O, Can M, Elmali E, Akan H (February 2006). "Cystatin C can be affected by nonrenal factors: a preliminary study on leukemia". Clin. Biochem. 39 (2): 115–118. doi:10.1016/j.clinbiochem.2005.10.009. PMID 16337174.
  17. ↑ Nakai K, Kikuchi M, Fujimoto K, et al. (April 2008). "Serum levels of cystatin C in patients with malignancy". Clin. Exp. Nephrol. 12 (2): 132–139. doi:10.1007/s10157-008-0043-8. PMID 18317874.
  18. ↑ Kos J, Stabuc B, Cimerman N, Brünner N (December 1998). "Serum cystatin C, a new marker of glomerular filtration rate, is increased during malignant progression". Clin. Chem. 44 (12): 2556–7. PMID 9836733.
  19. ↑ Fricker M, Wiesli P, Brändle M, Schwegler B, Schmid C (May 2003). "Impact of thyroid dysfunction on serum cystatin C". Kidney Int. 63 (5): 1944–1947. doi:10.1046/j.1523-1755.2003.00925.x. PMID 12675875.
  20. ↑ Manetti L, Pardini E, Genovesi M, et al. (April 2005). "Thyroid function differently affects serum cystatin C and creatinine concentrations". J. Endocrinol. Invest. 28 (4): 346–9. doi:10.1007/bf03347201. PMID 15966508. Archived from the original on 2008-06-08.
  21. ↑ Wiesli P, Schwegler B, Spinas GA, Schmid C (December 2003). "Serum cystatin C is sensitive to small changes in thyroid function". Clin. Chim. Acta. 338 (1–2): 87–90. doi:10.1016/j.cccn.2003.07.022. PMID 14637271.
  22. ↑ Risch L, Herklotz R, Blumberg A, Huber AR (November 2001). "Effects of glucocorticoid immunosuppression on serum cystatin C concentrations in renal transplant patients". Clin. Chem. 47 (11): 2055–9. PMID 11673383.
  23. ↑ Cimerman N, Brguljan PM, Krasovec M, Suskovic S, Kos J (October 2000). "Serum cystatin C, a potent inhibitor of cysteine proteinases, is elevated in asthmatic patients". Clin. Chim. Acta. 300 (1–2): 83–95. doi:10.1016/S0009-8981(00)00298-9. PMID 10958865.
  24. ↑ Bökenkamp A, van Wijk JA, Lentze MJ, Stoffel-Wagner B (July 2002). "Effect of corticosteroid therapy on serum cystatin C and beta2-microglobulin concentrations". Clin. Chem. 48 (7): 1123–6. PMID 12089191.
  25. ↑ Knight EL, Verhave JC, Spiegelman D, et al. (April 2004). "Factors influencing serum cystatin C levels other than renal function and the impact on renal function measurement". Kidney Int. 65 (4): 1416–1421. doi:10.1111/j.1523-1755.2004.00517.x. PMID 15086483.
  26. ↑ Odden MC, Scherzer R, Bacchetti P, et al. (November 2007). "Cystatin C level as a marker of kidney function in human immunodeficiency virus infection: the FRAM study". Arch. Intern. Med. 167 (20): 2213–2219. doi:10.1001/archinte.167.20.2213. PMC 3189482. PMID 17998494.[permanent dead link]
  27. ↑ Collé A, Tavera C, Prévot D, et al. (1992). "Cystatin C levels in sera of patients with human immunodeficiency virus infection. A new avidin-biotin ELISA assay for its measurement". J Immunoassay. 13 (1): 47–60. doi:10.1080/15321819208019824. PMID 1569212.
  28. ↑ Jaroszewicz J, Wiercinska-Drapalo A, Lapinski TW, Prokopowicz D, Rogalska M, Parfieniuk A (2006). "Does HAART improve renal function? An association between serum cystatin C concentration, HIV viral load and HAART duration". Antivir. Ther. (Lond.). 11 (5): 641–5. PMID 16964834.
  29. ↑ Strevens H, Wide-Swensson D, Torffvit O, Grubb A (2002). "Serum cystatin C for assessment of glomerular filtration rate in pregnant and non-pregnant women. Indications of altered filtration process in pregnancy". Scand. J. Clin. Lab. Invest. 62 (2): 141–147. doi:10.1080/003655102753611771. PMID 12004930.
  30. ↑ Akbari A, Lepage N, Keely E, et al. (May 2005). "Cystatin-C and beta trace protein as markers of renal function in pregnancy". BJOG. 112 (5): 575–578. doi:10.1111/j.1471-0528.2004.00492.x. PMID 15842279.
  31. ↑ Sjöström P, Tidman M, Jones I (2005). "Determination of the production rate and non-renal clearance of cystatin C and estimation of the glomerular filtration rate from the serum concentration of cystatin C in humans". Scand. J. Clin. Lab. Invest. 65 (2): 111–124. doi:10.1080/00365510510013523. PMID 16025834.
  32. ↑ Tonelli M, Wiebe N, Culleton B, et al. (July 2006). "Chronic kidney disease and mortality risk: a systematic review". J. Am. Soc. Nephrol. 17 (7): 2034–2047. doi:10.1681/ASN.2005101085. PMID 16738019.
  33. ↑ Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY (September 2004). "Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization". N. Engl. J. Med. 351 (13): 1296–1305. doi:10.1056/NEJMoa041031. PMID 15385656.
  34. ↑ Zethelius B, Berglund L, Sundström J, et al. (May 2008). "Use of multiple biomarkers to improve the prediction of death from cardiovascular causes". N. Engl. J. Med. 358 (20): 2107–2116. doi:10.1056/NEJMoa0707064. PMID 18480203.
  35. ↑ Shlipak MG, Sarnak MJ, Katz R, et al. (May 2005). "Cystatin C and the risk of death and cardiovascular events among elderly persons". N. Engl. J. Med. 352 (20): 2049–2060. doi:10.1056/NEJMoa043161. PMID 15901858.
  36. ↑ Ix JH, Shlipak MG, Chertow GM, Whooley MA (January 2007). "Association of cystatin C with mortality, cardiovascular events, and incident heart failure among persons with coronary heart disease: data from the Heart and Soul Study". Circulation. 115 (2): 173–179. doi:10.1161/CIRCULATIONAHA.106.644286. PMC 2771187. PMID 17190862.
  37. ↑ Deo R, Fyr CL, Fried LF, et al. (January 2008). "Kidney dysfunction and fatal cardiovascular disease--an association independent of atherosclerotic events: results from the Health, Aging, and Body Composition (Health ABC) study". Am. Heart J. 155 (1): 62–68. doi:10.1016/j.ahj.2007.08.012. PMID 18082491.
  38. ↑ Koenig W, Twardella D, Brenner H, Rothenbacher D (February 2005). "Plasma concentrations of cystatin C in patients with coronary heart disease and risk for secondary cardiovascular events: more than simply a marker of glomerular filtration rate". Clin. Chem. 51 (2): 321–327. doi:10.1373/clinchem.2004.041889. PMID 15563478.
  39. ↑ Jernberg T, Lindahl B, James S, Larsson A, Hansson LO, Wallentin L (October 2004). "Cystatin C: a novel predictor of outcome in suspected or confirmed non-ST-elevation acute coronary syndrome". Circulation. 110 (16): 2342–2348. doi:10.1161/01.CIR.0000145166.44942.E0. PMID 15477399.
  40. ↑ Luc G, Bard JM, Lesueur C, et al. (April 2006). "Plasma cystatin-C and development of coronary heart disease: The PRIME Study". Atherosclerosis. 185 (2): 375–380. doi:10.1016/j.atherosclerosis.2005.06.017. PMID 16046222.
  41. ↑ Servais A, Giral P, Bernard M, Bruckert E, Deray G, Isnard Bagnis C (May 2008). "Is serum cystatin-C a reliable marker for metabolic syndrome?". Am. J. Med. 121 (5): 426–432. doi:10.1016/j.amjmed.2008.01.040. PMID 18456039.
  42. ↑ Menon V, Shlipak MG, Wang X, et al. (July 2007). "Cystatin C as a risk factor for outcomes in chronic kidney disease". Annals of Internal Medicine. 147 (1): 19–27. doi:10.7326/0003-4819-147-1-200707030-00004. PMID 17606957.
  43. ↑ Sarnak MJ, Katz R, Fried LF, et al. (January 2008). "Cystatin C and aging success". Arch. Intern. Med. 168 (2): 147–153. doi:10.1001/archinternmed.2007.40. PMC 2871318. PMID 18227360.[permanent dead link]
  44. ↑ Djoussé L, Kurth T, Gaziano JM (January 2008). "Cystatin C and risk of heart failure in the Physicians' Health Study (PHS)". Am. Heart J. 155 (1): 82–86. doi:10.1016/j.ahj.2007.08.023. PMC 2179893. PMID 18082494.
  45. ↑ O'Hare AM, Newman AB, Katz R, et al. (2005). "Cystatin C and incident peripheral arterial disease events in the elderly: results from the Cardiovascular Health Study". Arch. Intern. Med. 165 (22): 2666–2670. doi:10.1001/archinte.165.22.2666. PMID 16344426.[permanent dead link]
  46. ↑ Stevens LA, Levey AS (May 2005). "Chronic kidney disease in the elderly--how to assess risk". N. Engl. J. Med. 352 (20): 2122–2124. doi:10.1056/NEJMe058035. PMID 15901867.
  47. ↑ Delanaye P, Cavalier E, Krzesinski JM (February 2008). "Cystatin C, renal function, and cardiovascular risk". Annals of Internal Medicine. 148 (4): 323. doi:10.7326/0003-4819-148-4-200802190-00023. PMID 18283218.
  48. ↑ Levy E, Lopez-Otin C, Ghiso J, Geltner D, Frangione B (May 1989). "Stroke in Icelandic patients with hereditary amyloid angiopathy is related to a mutation in the cystatin C gene, an inhibitor of cysteine proteases". J. Exp. Med. 169 (5): 1771–1778. doi:10.1084/jem.169.5.1771. PMC 2189307. PMID 2541223.
  49. ↑ Levy E, Jaskolski M, Grubb A (January 2006). "The role of cystatin C in cerebral amyloid angiopathy and stroke: cell biology and animal models". Brain Pathol. 16 (1): 60–70. doi:10.1111/j.1750-3639.2006.tb00562.x. PMID 16612983.
  50. ↑ Mi W, Pawlik M, Sastre M, et al. (December 2007). "Cystatin C inhibits amyloid-beta deposition in Alzheimer's disease mouse models". Nat. Genet. 39 (12): 1440–1442. doi:10.1038/ng.2007.29. PMID 18026100.
  51. ↑ Kaeser SA, Herzig MC, Coomaraswamy J, et al. (December 2007). "Cystatin C modulates cerebral beta-amyloidosis". Nat. Genet. 39 (12): 1437–1439. doi:10.1038/ng.2007.23. PMID 18026102.
  52. ↑ Bertram L, McQueen MB, Mullin K, Blacker D, Tanzi RE (January 2007). "Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database". Nat. Genet. 39 (1): 17–23. doi:10.1038/ng1934. PMID 17192785.
  53. ↑ Chuo LJ, Sheu WH, Pai MC, Kuo YM (2007). "Genotype and plasma concentration of cystatin C in patients with late-onset Alzheimer disease". Dement Geriatr Cogn Disord. 23 (4): 251–257. doi:10.1159/000100021. PMID 17310123.
  54. ↑ Del Boccio P, Pieragostino D, Lugaresi A, et al. (August 2007). "Cleavage of cystatin C is not associated with multiple sclerosis". Annals of Neurology. 62 (2): 201–204. doi:10.1002/ana.20968. PMID 17006926.
  55. ↑ Shi GP, Sukhova GK, Grubb A, et al. (November 1999). "Cystatin C deficiency in human atherosclerosis and aortic aneurysms" (PDF). J. Clin. Invest. 104 (9): 1191–1197. doi:10.1172/JCI7709. PMC 409823. PMID 10545518.
  56. ↑ Abisi S, Burnand KG, Waltham M, Humphries J, Taylor PR, Smith A (December 2007). "Cysteine protease activity in the wall of abdominal aortic aneurysms". J. Vasc. Surg. 46 (6): 1260–1266. doi:10.1016/j.jvs.2007.08.015. PMID 18155003.
  57. ↑ Abdul-Hussien H, Soekhoe RG, Weber E, et al. (March 2007). "Collagen degradation in the abdominal aneurysm: a conspiracy of matrix metalloproteinase and cysteine collagenases" (– Scholar search). Am. J. Pathol. 170 (3): 809–817. doi:10.2353/ajpath.2007.060522. PMC 1864891. PMID 17322367.[dead link]
  58. ↑ Gacko M, Chyczewski L, Chrostek L (1999). "Distribution, activity and concentration of cathepsin B and cystatin C in the wall of aortic aneurysm". Pol J Pathol. 50 (2): 83–6. PMID 10481531.
  59. ↑ Eriksson P, Jones KG, Brown LC, Greenhalgh RM, Hamsten A, Powell JT (January 2004). "Genetic approach to the role of cysteine proteases in the expansion of abdominal aortic aneurysms". Br J Surg. 91 (1): 86–89. doi:10.1002/bjs.4364. PMID 14716800.
  60. ↑ Lindholt JS, Erlandsen EJ, Henneberg EW (November 2001). "Cystatin C deficiency is associated with the progression of small abdominal aortic aneurysms". Br J Surg. 88 (11): 1472–1475. doi:10.1046/j.0007-1323.2001.01911.x. PMID 11683743.
  61. ↑ Zurdel J, Finckh U, Menzer G, Nitsch RM, Richard G (February 2002). "CST3 genotype associated with exudative age related macular degeneration". Br J Ophthalmol. 86 (2): 214–219. doi:10.1136/bjo.86.2.214. PMC 1771004. PMID 11815350.
  62. ↑ Im E, Kazlauskas A (March 2007). "The role of cathepsins in ocular physiology and pathology". Exp. Eye Res. 84 (3): 383–388. doi:10.1016/j.exer.2006.05.017. PMID 16893541.
  63. ↑ Strojan P, Oblak I, Svetic B, Smid L, Kos J (May 2004). "Cysteine proteinase inhibitor cystatin C in squamous cell carcinoma of the head and neck: relation to prognosis". Br. J. Cancer. 90 (10): 1961–1968. doi:10.1038/sj.bjc.6601830. PMC 2409457. PMID 15138478.
  64. ↑ Kos J, Krasovec M, Cimerman N, Nielsen HJ, Christensen IJ, Brünner N (February 2000). "Cysteine proteinase inhibitors stefin A, stefin B, and cystatin C in sera from patients with colorectal cancer: relation to prognosis". Clin. Cancer Res. 6 (2): 505–11. PMID 10690531.
  65. ↑ Strevens H, Wide-Swensson D, Grubb A, et al. (September 2003). "Serum cystatin C reflects glomerular endotheliosis in normal, hypertensive and pre-eclamptic pregnancies". BJOG. 110 (9): 825–830. doi:10.1111/j.1471-0528.2003.02051.x. PMID 14511964.
  66. ↑ Franceschini N, Qiu C, Barrow DA, Williams MA (2008). "Cystatin C and preeclampsia: a case control study". Ren Fail. 30 (1): 89–95. doi:10.1080/08860220701742229. PMID 18197549.
  67. ↑ Kristensen K, Wide-Swensson D, Schmidt C, et al. (2007). "Cystatin C, beta-2-microglobulin and beta-trace protein in pre-eclampsia". Acta Obstet Gynecol Scand. 86 (8): 921–926. doi:10.1080/00016340701318133. PMID 17653875.
  68. ↑ Kristensen K, Larsson I, Hansson SR (March 2007). "Increased cystatin C expression in the pre-eclamptic placenta". Mol. Hum. Reprod. 13 (3): 189–195*. doi:10.1093/molehr/gal111. PMID 17227816.
  69. ↑ 69.0 69.1 Croda-Todd MT, Soto-Montano XJ, Hernández-Cancino PA, Juárez-Aguilar E (September 2007). "Adult cystatin C reference intervals determined by nephelometric immunoassay". Clin. Biochem. 40 (13–14): 1084–1087. doi:10.1016/j.clinbiochem.2007.05.011. PMID 17624320.
  70. ↑ Lamb EJ, O'Riordan SE, Webb MC, Newman DJ (November 2003). "Serum cystatin C may be a better marker of renal impairment than creatinine". J Am Geriatr Soc. 51 (11): 1674–1675. doi:10.1046/j.1532-5415.2003.515244.x. PMID 14687406.
  71. ↑ Peake M, Whiting M (November 2006). "Measurement of serum creatinine - current status and future goals". Clin Biochem Rev. 27 (4): 173–84. PMC 1784008. PMID 17581641.
  72. ↑ Myers GL, Miller WG, Coresh J, et al. (January 2006). "Recommendations for improving serum creatinine measurement: a report from the Laboratory Working Group of the National Kidney Disease Education Program". Clin. Chem. 52 (1): 5–18. doi:10.1373/clinchem.2005.0525144. PMID 16332993.
  73. ↑ 73.0 73.1 73.2 Köttgen A, Selvin E, Stevens LA, Levey AS, Van Lente F, Coresh J (March 2008). "Serum cystatin C in the United States: the Third National Health and Nutrition Examination Survey (NHANES III)". Am. J. Kidney Dis. 51 (3): 385–394. doi:10.1053/j.ajkd.2007.11.019. PMID 18295054.
  74. ↑ 74.0 74.1 Finney H, Newman DJ, Thakkar H, Fell JM, Price CP (January 2000). "Reference ranges for plasma cystatin C and creatinine measurements in premature infants, neonates, and older children". Arch. Dis. Child. 82 (1): 71–75. doi:10.1136/adc.82.1.71. PMC 1718178. PMID 10630919.
  75. ↑ Ognibene A, Mannucci E, Caldini A, et al. (June 2006). "Cystatin C reference values and aging". Clin. Biochem. 39 (6): 658–661. doi:10.1016/j.clinbiochem.2006.03.017. PMID 16730690.
  76. ↑ Filler G, Bökenkamp A, Hofmann W, Le Bricon T, Martínez-Brú C, Grubb A (January 2005). "Cystatin C as a marker of GFR--history, indications, and future research". Clin. Biochem. 38 (1): 1–8. doi:10.1016/j.clinbiochem.2004.09.025. PMID 15607309.
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  78. ↑ Muntner P, Winston J, Uribarri J, Mann D, Fox CS (April 2008). "Overweight, obesity, and elevated serum cystatin C levels in adults in the United States". Am. J. Med. 121 (4): 341–348. doi:10.1016/j.amjmed.2008.01.003. PMC 3049932. PMID 18374694.
  79. ↑ "Entrez Gene: CST3 cystatin C (amyloid angiopathy and cerebral hemorrhage)".
  80. ↑ Hwang SJ, Yang Q, Meigs JB, Pearce EN, Fox CS (2007). "A genome-wide association for kidney function and endocrine-related traits in the NHLBI's Framingham Heart Study". BMC Med. Genet. 8 Suppl 1: S10. doi:10.1186/1471-2350-8-S1-S10. PMC 1995611. PMID 17903292. Archived from the original on 2008-06-12.
  81. ↑ Janowski R, Kozak M, Jankowska E, et al. (April 2001). "Human cystatin C, an amyloidogenic protein, dimerizes through three-dimensional domain swapping". Nature Structural & Molecular Biology. 8 (4): 316–320. doi:10.1038/86188. PMID 11276250.
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  83. ↑ Löfberg H, Grubb AO (November 1979). "Quantitation of gamma-trace in human biological fluids: indications for production in the central nervous system". Scand. J. Clin. Lab. Invest. 39 (7): 619–626. doi:10.3109/00365517909108866. PMID 119302.
  84. ↑ Grubb A, Simonsen O, Sturfelt G, Truedsson L, Thysell H (1985). "Serum concentration of cystatin C, factor D and beta 2-microglobulin as a measure of glomerular filtration rate". Acta Med Scand. 218 (5): 499–503. doi:10.1111/j.0954-6820.1985.tb08880.x. PMID 3911736.
  85. ↑ Simonsen O, Grubb A, Thysell H (April 1985). "The blood serum concentration of cystatin C (gamma-trace) as a measure of the glomerular filtration rate". Scand. J. Clin. Lab. Invest. 45 (2): 97–101. doi:10.3109/00365518509160980. PMID 3923607.
  86. ↑ Shlipak MG, Matsushita K, Ärnlöv J, Inker LA, Katz R, Polkinghorne KR, Rothenbacher D, Sarnak MJ, Astor BC, Coresh J, Levey AS, Gansevoort RT (2013). "Cystatin C versus creatinine in determining risk based on kidney function". NEJM. 369: 932–943. doi:10.1056/NEJMoa1214234. PMC 3993094. PMID 24004120.

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